Cough Reflex Research Articles

Evaluation of Oropharyngeal Dysphagia in Patients Who Underwent Percutaneous Endoscopic Gastrostomy: Stratification Risk of Pneumonia.

Aspiration pneumonia is the most common cause of death in patients who undergo percutaneous endoscopic gastrostomy (PEG). This study aims to evaluate the severity of oropharyngeal dysphagia and predict the risk of pneumonia in such patients, using upper gastrointestinal endoscopy. Endoscope examined the pharyngolaryngeal region in patients who underwent PEG. The severity of oropharyngeal dysphagia was evaluated according to the amount and location of pooling of secretions in the pharyngolaryngeal region. Overall, 55 patients showed absent or minimal amount of secretions (control group), 10 patients showed moderate-to-large amounts of secretions filling the pyriform sinus (pharyngeal group), and 23 patients showed secretions entering the laryngeal vestibule (laryngeal group). Demographic data, swallowing level scale, and occurrence of pneumonia were recorded. The incidence of pneumonia was the highest in the pharyngeal group (70.0%), followed by that in the laryngeal (60.9%) and control groups (30.9%; P=0.010). Multivariable regression showed that risk of pneumonia was significantly higher in the pharyngeal and laryngeal groups. Cumulative incidence rate of pneumonia was significantly higher in the laryngeal and pharyngeal groups than in the control group (log-rank test, P=0.001). Mortality rate was significantly higher in patients with suboptimal protective cough reflex than in others (50.0% vs 5.9%, P=0.034). Accumulation of abnormal amounts of secretions in the pyriform sinus or in the laryngeal vestibule increased the risk of the hospital admission following pneumonia in patients who underwent PEG. The mortality rate was higher in patients with suboptimal protective cough reflex.

Comparison of Central Venous Pressure (Cvp) Score among Patients on Mechanical Ventilator with Head of Bed (Hob) Elevation 30O; Neutral, Right, and Left Side Positions

Early mobilization is important for critical patients to improve cough reflexes, eliminate bronchial secretions, facilitate work of mucociliary drainage muscles, and to prevent associated pneumonia ventilators and pressure sores. However, at the same time the patient often experiences vital signs change due to fluctuating conditions. Central Venous Pressure (CVP) measurement is oftenly needed to monitor central circulatory system. Unfortunately, in the clinical setting, the patient’s position must be changed first in a 30o neutral head of bed (HoB) position rather than left or right side HoB position. This study aims to examine the differences in of CVP score among patients on mechanical ventilation at HoB position elevation 30o in a neutral, right side, and left side position. This quantitative comparative study involved 24 subjects who were recruited consecutively. Data were analyzed using ANOVA. The results showed that the mean CVP value at neutral HoB position elevation was 13.5 ± 3.96, right sight HoB elevation was 12.8 ± 4.16, and left side HoB elevation was 14.4 ± 4.17. There was a significant difference (p <0.05) among those three positions. Post hoc analysis test found the HoB position 30o neutral vs left side possition was higher and signifficantly difference with HoB elevation 30o neutral vs right side positions (p<0.05). This study suggested nurses need to consider the change of CVP values while changing patiens’ position of HoB elevation 30o neutral, right side, and left side positions. Athough there was statistically difference among three positions, in fact, the value difference was less than 1 cmH2O which clinically did not see any differences.

Evaluation of the Effect of Various Radiotherapy Modalities on Swallowing Function in Patients With Nasopharyngeal Cancer.

The objective of this study was to compare the effect of curative 3-dimensional (3D) conformal radio-chemotherapy and intensity-modulated radiotherapy (IMRT) modalities on swallowing function in patients with nasopharyngeal cancer. Ten patients receiving 3D conformal radiotherapy and 10 patients receiving curative radiotherapy with IMRT, who were admitted for malignancy control for nasopharyngeal cancer, were included in the study. Swallowing functions were determined by flexible fiberoptic endoscopic evaluation. Premature spillage, retention pooling, penetration, aspiration, and reflex cough were evaluated. No statistically significant difference was found between patients receiving 3D conformal radiotherapy and IMRT regarding the scores of premature spillage, retention pooling, penetration, and aspiration with 3, 5, and 10 mL water and 5 mL yoghurt and fish crackers (P > .05). Velopharyngeal insufficiency or delayed onset of swallowing reflex was not found in any of the patients (P > .05). No significant difference was found between the groups in terms of the symptoms regarding subjective evaluation of swallowing (P > .05). Swallowing function did not differ among patients receiving IMRT and 3D conformal radiotherapy. Further studies with a larger sample size are warranted in order to verify the results.

MAPPING NEURAL CIRCUITS CRITICAL TO UPPER AIRWAY FUNCTION AND BREATHING‐SWALLOWING COORDINATION

Upper airway control and the coordination between swallowing and breathing are essential to avoid the introduction of food or liquids into the lungs. The neural networks underlying upper airway control and swallowing coordination is poorly understood. However, perturbations to these networks may play a role in Sudden Infant Death Syndrome, obstructive sleep apnea, and neurodegenerative disorders such as Parkinson's disease where as much as 44% mortality is attributed to aspiration pneumonia. Thus, there is a clear need to better understand the neural mechanisms that underlie upper airway control, swallowing coordination, and cough reflex throughout life.Though GABAergic signaling is critical to modulate breathing, the functional organization of widespread GABAergic neurons throughout the brainstem remains unclear. We hypothesize that the adult GABAergic system is integrated into distinct functional modules within the brainstem respiratory network aligned along early hindbrain rhombomeric origins. To test this hypothesis, we aim to genetically subdivide the adult brainstem GABAergic system based on their embryonic rhombomere of origin for functional and anatomical mapping studies through the use of intersectional genetic techniques and new chemo‐genetic (DREADD) mouse lines combined with whole body barometric plethysmography and metabolic monitoring.Preliminary studies indicate that inhibitory DREADD hM4De‐mediated perturbation of systemwide GABAergic neurons (Vgat_FLPo positive neurons) results in increased respiratory output and greater breathing instability while excitatory DREADD hM3D‐mediated systemwide perturbation results in increased sighs and decreased metabolic demand. Examination of the respiratory waveform shows mid‐inspiratory pauses indicative of poor glottal control and increased incidences of cough and expiratory reflex movements. Initial results from rhombomere GABAergic mapping studies suggest that GABAergic involvement in adult chemosensory reflexes may be organized along developmental rhombomeres during embryogenesis.Support or Funding InformationMcNair Medical InstituteThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Potassium Channel Subtypes that Regulate Airway Vagal Sensory Nerve Excitability

Vagal sensory afferent nerves innervating the respiratory tracts play a defensive and homeostatic role in cardiopulmonary physiology. The majority of vagal afferent nerves in the airways are nociceptive in nature. Exaggerated activation of airway nociceptive nerve fibers by inflammatory mediators and other potentially noxious stimuli can lead to chronic cough, dyspnea, and aberrant reflex responses such as airway constriction and excessive mucus secretion. Most investigations on airway vagal nociceptive nerves have focused on the mediators and ion channels that underlie their activation while very little research attention has been given to the inhibitory K+ channels that operate at resting and/or subthreshold membrane potentials. These channels serve as brakes against excessive activation. In this study, we investigate the role of KCNQ/KV7/M‐channels, KCNA/KV1 channels and KCNK/two‐pore domain K+ (K2P) channels in regulating the intrinsic excitability of mouse nodose neurons and airway C‐fibers. Ultra‐low input RNA sequencing experiments showed that both lung‐specific and general population of isolated mouse nodose neurons express members of KV7, KV1, as well as TWIK, TASK and TREK subfamilies of K2P channels. Patch clamp recordings revealed an XE991‐sensitive KCNQ/KV7/M‐channel current (IM), α‐dendrotoxin (DTX)‐sensitive KV1‐mediated D‐current (ID) and an extracellular acidification‐inhibited TASK current in the majority of nodose neurons examined. IM activates around −65 mV with V1/2 for activation being at −38±3 mV. ID isolated with 10 nM α‐DTX has two components, and the low‐threshold component activates between −70 and −60 mV. At a holding potential of −60 mV, lowering the pH of the bath solution from 7.3 to 5.5 abolished the outward TASK current. The resting potential of mouse nodose neurons determined by perforated patch clamp technique averaged at −61±0.5 mV (n=65). Bath application of 10 μM M‐channel inhibitor XE991 or 30 nM ID channel blocker α‐DTX, or bath acidification led to a depolarization of 2 to 15 mV. Extracellular recordings of nodose neuron activities in the isolated and perfused vagus‐innervated mouse lung preparation revealed that the M‐channel opener retigabine applied locally to the lungs abolished the α,β‐meATP‐evoked action potential firing in pulmonary C‐fiber terminals. In the same kind of vagus‐lung preparations, application of 100 nM α‐DTX to the mouse lungs elicited action potential firing in about 20% of nodose fibers in the lungs as detected by two‐photon microscopy using mice expressing the Ca2+ indicator GCaMP6 under the Pirt promoter. In conclusion, our results indicate that KV7/M‐channels, KV1/ID channels and K2P/TASK channels contribute to maintaining the negative resting membrane potential in mouse nodose neurons and serve as a brake on their activation. Down regulation of these channels in visceral inflammatory diseases may contribute to sensory hyperexcitability. Alternatively, approaches enhancing the function of these K+ channels may be beneficial in the management of inflammatory diseases associated with vagal afferent hyperexcitability.(This study was conducted in conformance with the FASEB Statement of Principles for the use of Animals in Research and Education).Support or Funding InformationR01 HL122228; R01 HL137807‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Influence of Codeine on Swallow in the Anesthetized Cat: Evidence for Peripheral and Central Actions of Opioids to Induce Dysregulation of Deglutition

Systemic administration of opioids has been associated with aspiration and swallow dysfunction in humans. The extent to which these outcomes are due to solely central, or both central and peripheral actions, of these drugs is unknown. Codeine is a commonly prescribed opioid that has both central and peripheral actions to affect the cough reflex in animal models. We speculated that systemic administration of codeine would induce dysfunctional swallowing and that this effect would have a peripheral component. Experiments were conducted in spontaneously breathing, anesthetized cats (n=19). The animals were tracheotomized and EMG electrodes were placed in upper airway and chest wall respiratory muscles for recording swallow related motor activity. The animals were allocated into three groups: vagal intact (VI), cervical vagotomy (CVx), and supra‐nodose ganglion vagotomy (SNVx). A dose‐response to intravenous codeine (0.1–10 mg/kg) was performed in each animal. Swallowing was elicited by injection of 3 ml of water into the oropharynx. Results demonstrated a significant dose‐related increase in spontaneous swallowing (per 7 minute period between doses) in each group (VI: vehicle 0.2±0.2 to 10 mg/kg codeine 6.6±4.0, SNVx: vehicle 0.2±0.2 to 10 mg/kg codeine 4.0±2.3, CVx: vehicle 2.3±1.3 to 13±6.0 10 mg/kg codeine). Additionally, the number of induced swallows after vehicle was significantly higher in the VI group than in SNVx (p<0.04), and in the CVx compared to the SNVx group at 10mg/kg (p<0.05). Codeine also demonstrated dose‐dependent effects on upper airway motor drive during the induced swallow trials. The thyropharyngeus muscle EMG activation was significantly increased in the VI and CVx groups by 2–4 fold in a dose‐related manner (p<0.01). Also, in the CVx group, the geniohyoid muscle EMG activation was significantly increased (p<0.05). Under control conditions the presence of spontaneous swallows is rare, and their presence in response to codeine supports a strong central action and likely a dysregulation of the inhibitory influences on the swallow pattern generator. Unlike cervical vagotomy, section of the vagus nerve rostral to the nodose ganglion eliminates superior laryngeal nerve afferents. At the highest dose of codeine, the reduced spontaneous swallow number in the SNVx group relative to CVx is consistent with a peripheral excitatory action of codeine either on pharyngeal/laryngeal receptors or in the nodose ganglion itself.Support or Funding InformationSupported by OT2OD023854‐01, HL109025, HL131716.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mechanisms Underlying the Stimulatory Effect of Inhaled Sulfur Dioxide on Rat Vagal Bronchopulmonary Sensory Nerves

Chronic exposure to sulfur dioxide (SO2), an air pollutant, can cause airway injury and lung diseases. Acute exposure to SO2 triggers cough and reflex bronchoconstriction, indicating a stimulatory effect of SO2 on airway sensory nerves. Indeed, a recent study in our lab has demonstrated that vagal bronchopulmonary C‐fibers are the primary target of inhaled SO2. This study was carried out to investigate the underlying mechanism of this stimulatory effect of SO2 on bronchopulmonary C‐fibers. Our results showed: 1) Inhalation of SO2 (1,000–2,000 ppm, 10 breaths) evoked a pronounced and reproducible stimulatory effect on pulmonary C‐fibers in anesthetized rats. 2) Pretreatment with an intravenous infusion of sodium bicarbonate (120 μmol/kg) raised the baseline arterial pH by 0.08 units, which profoundly diminished the stimulatory effect of SO2 on pulmonary C‐fibers by 83.9%. 3) This stimulatory effect of SO2 was also significantly attenuated by a pretreatment with amiloride (a blocker of acid‐sensing ion channels, ASICs; 11 μmol/kg) alone (Δ = 70.7%); AMG9810 (an antagonist of transient receptor potential vanilloid type‐1, TRPV1; 10 μmol/kg) alone (Δ = 76.7%); and by a combination of amiloride and AMG9810 (Δ = 91.4%). 4) To further investigate if this stimulatory effect is generated by a direct action of SO2 on sensory nerves, the change in intracellular Ca2+ concentration, [Ca2+]i, was measured in isolated rat vagal pulmonary sensory neurons. Perfusion with extracellular fluid saturated with SO2 (1,000 and 2,000 ppm) evoked a significant increase in [Ca2+]i in a concentration‐dependent manner in these neurons, and these responses to SO2 were markedly suppressed by a combined pretreatment with amiloride and AMG9810. 5) In addition, inhalation of SO2 (300 and 600 ppm for 5 min) evoked cough reflex responses consistently in awake mice in a concentration‐dependent manner; the cough responses were almost completely prevented by a pretreatment with amiloride aerosol inhalation (5 mM for 4 min) in TRPV1‐knockout mice. In conclusion, this study suggested that inhalation of SO2 lowered the pH in airway/lung tissues, which exerted a stimulatory effect on vagal bronchopulmonary C‐fibers by activating both ASICs and TRPV1 channels.Support or Funding InformationNIH grants AI123832 & UL1TR001998This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cohort Study on Laryngeal Cough Reflex, Respiratory Disease, and Death: A Mediation Analysis

ObjectiveTo estimate quantitatively whether the presence of cough associated with dysphagia (laryngeal cough reflex) increased mortality through respiratory disease among community-dwelling older Japanese. DesignA 6-year follow-up prospective cohort study (from 2010 to 2017). SettingThirteen municipalities in Japan. ParticipantsCommunity-dwelling individuals aged 65 years or older (N = 32,682). MeasuresThe baseline survey was conducted through self-reported questionnaire. Exposure was experience of laryngeal cough reflex while drinking. The outcome was all-cause mortality. All covariates were selected from demographic, socioeconomic variables, baseline health and functional status, smoking, alcohol drinking, number of remaining teeth, and stroke. The mediator variable was respiratory disease. Cox proportional hazards regression was used to estimate hazard ratios (HRs) for mortality. Parametric mediation analysis was conducted to estimate the effect of laryngeal cough reflex on the mean residual time to death mediated through respiratory disease. ResultsAmong the 32,682 participants (mean age = 74.1 years, standard deviation = 5.9 years), 5550 (17.0%) experienced laryngeal cough reflex at baseline. A total of 4037 deaths occurred. Crude mortality rates of the participants with or without laryngeal cough reflex were 16.3% and 11.6%, respectively. After adjusting for covariates, laryngeal cough reflex [HR = 1.10; 95% confidence interval (CI) = 1.02 to 1.19] and respiratory disease (HR = 1.80; 95% CI = 1.62 to 2.00) were associated with mortality. The mediation analysis showed that respiratory disease significantly (P < .001) and partially mediated the association between laryngeal cough reflex, an indicator of 1 or more conditions such as chronic aspiration and mortality. Conclusions/ImplicationsLaryngeal cough reflex was a prevalent condition, and it was associated with all-cause mortality in community-dwelling older Japanese individuals. Clinicians could contribute to reduce mortality risk by addressing swallowing function problems using their interprofessional collaboration team (speech-language pathologist, dentist, rehabilitation doctor, otolaryngologist, respiratory physician, and gerontologist).

BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration

BLU-5937 is a small molecule that was shown to be a potent, selective and non-competitive P2X3 homotrimeric receptor antagonist. P2X3 receptors are ATP ion-gated channels located on primary afferent neurons. ATP released from damaged or inflamed tissues in the airways acts on P2X3 receptors of primary afferent neurons, triggering depolarization and action potentials that are transmitted centrally and interpreted as urge to cough. There are strong preclinical and clinical evidence supporting the role of P2X3 receptors in hypersensitization of the cough reflex, leading to chronic cough. By inhibiting P2X3 receptors on the primary sensory neurons, BLU-5937 would inhibit the hypersensitization of the cough reflex and, hence, the exaggerated cough experienced in chronic cough patients. BLU-5937 is being developed for the treatment of unexplained, refractory chronic cough.The high potency and selectivity of BLU-5937 for P2X3 homotrimeric receptors was demonstrated in vitro by inhibiting αβ-meATP-evoked P2X3 or P2X2/3 receptor activity in cloned human hP2X3 and hP2X2/3 channels expressed in mammalian cells. The IC50 of BLU-5937 for hP2X3 homotrimeric and hP2X2/3 heterotrimeric receptors was established at 25 nM and >24 μM, respectively. Furthermore, BLU-5937 (500 nM) was able to block αβ-meATP-induced sensitization and firing activity of isolated primary nociceptors in rat dorsal root ganglions (DRGs), through P2X3 homotrimeric receptor antagonism.In a guinea pig cough model, BLU-5937 (0.3, 3 and 30 mg/kg, oral) significantly reduced, in a dose-dependent fashion, the histamine-induced enhancement in the number of citric acid-induced coughs. BLU-5937 (3 and 30 mg/kg, oral) was also shown to reduce significantly and dose-dependently the ATP-induced enhancement of citric acid-induced coughs in the guinea pig. These anti-tussive effects were obtained at a plasma concentration known to block P2X3 homotrimeric receptors, but at concentration 50-fold lower than that required to block P2X2/3 heterotrimeric receptors. These results indicate that the anti-tussive effect of BLU-5937 is primarily mediated through the inhibition of P2X3 homotrimeric receptors.In a rat behavioral taste model, BLU-5937 (10–20 mg/kg, IP) did not alter taste perception as compared to control animals. In the same experiment, N-00588 (10–20 mg/kg, IP), a weakly selective antagonist for P2X3 versus P2X2/3 receptors, had a significant inhibitory effect on taste perception. Pharmacokinetic analysis of drug plasma concentrations showed that BLU-5937 did not affect taste function at concentrations up to 30 times the IC50 for P2X3. These results suggest that N-00588 achieved systemic concentration that blocked P2X3 and P2X2/3 receptors expressed on gustatory nerve ending innervating taste buds. The lack of effect of BLU-5937, even at high doses, on taste perception may be attributed to its higher selectivity for the P2X3 versus P2X2/3 receptors on the taste buds.The safety, tolerability and pharmacokinetic profile of BLU-5937 was assessed in a battery of preclinical studies and have revealed that BLU-5937 exhibits excellent drug-like characteristics, including good oral bioavailability, low predicted clearance in human, no blood-brain barrier permeability and high safety margin versus human predicted efficacious exposure. BLU-5937 is currently in clinical phase I development stage.In conclusion, BLU-5937 was selected as a drug candidate for the treatment of chronic cough due to its high potency and selectivity for P2X3 homotrimeric receptors, strong anti-tussive effects, excellent tolerability and predicted pharmacokinetic properties in humans.

Pathophysiological Mechanisms of Asthma.

The recent Lancet commission has highlighted that “asthma” should be used to describe a clinical syndrome of wheeze, breathlessness, chest tightness, and sometimes cough. The next step is to deconstruct the airway into components of fixed and variable airflow obstruction, inflammation, infection and altered cough reflex, setting the airway disease in the context of extra-pulmonary co-morbidities and social and environmental factors. The emphasis is always on delineating treatable traits, including variable airflow obstruction caused by airway smooth muscle constriction (treated with short- and long-acting β-2 agonists), eosinophilic airway inflammation (treated with inhaled corticosteroids) and chronic bacterial infection (treated with antibiotics with benefit if it is driving the disease). It is also important not to over-treat the untreatable, such as fixed airflow obstruction. These can all be determined using simple, non-invasive tests such as spirometry before and after acute administration of a bronchodilator (reversible airflow obstruction); peripheral blood eosinophil count, induced sputum, exhaled nitric oxide (airway eosinophilia); and sputum or cough swab culture (bacterial infection). Additionally, the pathophysiology of risk domains must be considered: these are risk of an asthma attack, risk of poor airway growth, and in pre-school children, risk of progression to eosinophilic school age asthma. Phenotyping the airway will allow more precise diagnosis and targeted treatment, but it is important to move to endotypes, especially in the era of increasing numbers of biologicals. Advances in -omics technology allow delineation of pathways, which will be particularly important in TH2 low eosinophilic asthma, and also pauci-inflammatory disease. It is very important to appreciate the difficulties of cluster analysis; a patient may have eosinophilic airway disease because of a steroid resistant endotype, because of non-adherence to basic treatment, and a surge in environmental allergen burden. Sophisticated –omics approaches will be reviewed in this manuscript, but currently they are not being used in clinical practice. However, even while they are being evaluated, management of the asthmas can and should be improved by considering the pathophysiologies of the different airway diseases lumped under that umbrella term, using simple, non-invasive tests which are readily available, and treating accordingly.

Long-term Swallowing Function, Pulmonary Complications, and Quality of Life after Supracricoid Laryngectomy.

Long-term effects of supracricoid laryngectomies are nowadays under discussion. The purpose of this study was to detect the prevalence of chronic aspiration and incidence of pulmonary complications, to investigate possible influencing factors, and to analyze dysphagia-related quality of life in a cohort of patients who recovered swallowing function after undergoing supracricoid laryngectomies. Retrospective observational study. San Raffaele Hospital, Vita-Salute University, Milan, Italy. A cohort of 39 patients who recovered swallowing function free of disease after a minimum 3-year follow-up period was retrospectively investigated between October and December 2017-clinically with the Pearson's Scale and M. D. Anderson Dysphagia Inventory and instrumentally with fiberoptic endoscopic evaluation of swallowing. Chronic aspiration was demonstrated in a significant portion of patients (clinically in 33.3% and instrumentally in 35.9%). Aspiration was influenced by advanced age at surgery (P = .020). Type of surgical procedure, resection of 1 arytenoid cartilage, postoperative rehabilitation with a speech-language therapist, radiotherapy, age at consultation, and length of follow-up did not influence the prevalence of aspiration. Pulmonary complications affected 5 patients; incidence of pulmonary complications was related to aspiration and was favored by poor laryngeal sensation/cough reflex. Aspiration significantly affected quality of life. Chronic aspiration is frequent and affects patients' quality of life. However, incidence of pulmonary complications is low; therefore, oral feeding should not be contraindicated for aspirating patients. Preservation of laryngeal sensation and cough reflex is mandatory to prevent pulmonary complications.

Independent Factors Contributing to Daytime and Nighttime Asthmatic Cough Refractory to Inhaled Corticosteroids.

Cough is a common feature of asthma, which is often resistant to inhaled corticosteroids (ICSs). The pathophysiology of this refractoriness may differ between daytime and nighttime asthmatic cough. We sought to identify factors contributing to ICS-refractory daytime and nighttime asthmatic cough. Sixty-seven patients with asthma presenting solely or predominantly with chronic cough were prospectively enrolled from April 2012 to December 2014. At baseline and 12 weeks after ICS treatment, the capsaicin cough threshold (C2, C5) and methacholine airway sensitivity and reactivity were examined. A visual analog scale (VAS) and numeric scores were used to evaluate daytime and nighttime cough symptoms separately. The Japanese version of the Leicester Cough Questionnaire was also completed. When either the VAS or numeric scores showed an improvement of ≥50% or ≥2 points, patients were considered responders to ICS treatment. Fifty-five patients were eligible for evaluation. Subjective cough indices improved significantly at 12 weeks after ICS treatment (P<.001). Multivariate analysis revealed that lower C2 significantly contributed to residual daytime cough (P=.04). Meanwhile, methacholine hyperreactivity and lower IgE levels were predictors of the nighttime residual cough (P=.002 and P=.03, respectively). Heightened cough reflex sensitivity is an independent factor of daytime asthmatic cough that is refractory to ICSs. In contrast, airway hyperreactivity and less atopic status contribute to ICS-refractory nighttime cough.

An arterially perfused brainstem preparation of guinea pig to study central mechanisms of airway defense

The perfused working heart brainstem preparation of rodents has become a widely used tool to study brainstem function. Here, we adapt this experimental technique for newborn guinea pigs (postnatal day 7–14) to develop a tool that enables investigation of airway defense mechanisms not observed in other rodents. The perfused guinea pig brainstem preparation generates a stable eupnea-like motor pattern recorded from the phrenic, recurrent laryngeal and intercostal nerves and basic cardio-respiratory reflexes, including the arterial chemoreceptor, the baroreceptor reflex. In addition a fictive laryngeal cough reflex can be reliably elicited after mechanical stimulation of the trachea. Single unit recordings within the ponto-medullary respiratory column show robust central respiratory neuronal activity. Additionally, as in other species ponto-medullary transection of the brainstem produces apneusis. The latter suggests that the preparation fully preserves ponto-medullary synaptic connectivity that is required for eupnea-like respiratory rhythm and pattern formation and the mediation of various cardio-respiratory reflexes. We conclude that this novel research tool provides an alternative to established rat and mouse preparations and may become a experimental tool for the investigation of central mechanisms that mediate laryngeal cough.

Effect of "Tongyuan" acupuncture treatment on success rate of extubation in stroke patients undergoing tracheotomy

To observe the impact of "Tongyuan" (regulating the Governor Vessel to tranquilize mental activities, conducting qi back to its origin) acupuncture treatment on cough reflex, pulmonary infection and swallowing function in stroke patients undergoing tracheotomy. Seventy-four cerebral stroke patients with tracheo-tomy were randomly allocated to scalp acupuncture and "Tongyuan" acupuncture groups (n=37 in each group). All the patients of the two groups received basic treatment, including treatment of primary diseases, routine nursing, respiratory muscle training, physical therapy, acupuncture of Chize (LU5), Quchi (LI11), Hegu (LI4), Weizhong (BL40), Zusanli (ST36). In addition, for patients of the scalp acupuncture group, the middle 2/5 of Dingnieqianxiexian (MS6), the middle 2/5 of Dingniehouxiexian (MS7) and Dingpangerxian (MS9) on the contralateral side of lesions were punctured with filiform needles. For patients of the "Tongyuan" acupuncture group, Baihui (GV20), Zhongwan (GV12), Guanyuan (CV4), Qihai (CV6), Tianshu (ST25), Feishu (BL13), Pishu (BL20) were needled. The treatment in both groups lasted 30 minutes each time, once daily, 6 times a week for 4 weeks. The cough reflex grading score (CRGS, assessed according to cough, independent expectoration, sputum suction), clinical pulmonary infection score (CPIS, assessed according to the body temperature, white blood cell count, airway secretion in 24 h, PaO2/FiO2, infiltration status, cultured pathogenic bacteria), and swallowing function were evaluated by a researcher who was blinded to the grouping and treatment procedures. The success rate of extubation was calculated in a week at the end of treatments. After the treatment, the CRGS and CPIS of both groups were apparently decreased in comparison with their own pre-treatment (P<0.05), suggesting an improvement of the cough reflex and pulmonary infection. Regarding the swallowing function, of the two 37 cases in the scalp acupuncture and "Tongyuan" acupuncture groups, 9(24.3%) and 19(51.4%) experienced marked improvement, 12(32.5%)and 14(37.8%) were effective, and 16(43.2%) and 4(10.8%)failed in the treatment, with the effective rate being 56.8% and 89.2%, respectively. In regard to the successful extubation, of the two 37 cases in the scalp acupuncture and "Tongyuan" acupuncture groups, 5(13.5%) and 11(29.8%)had a marked improvement, 10(27.0%)and 18(48.6%)were effective, and 22(59.5%)and 8(21.6%)failed, with the effective rate being 40.5% and 78.4%, respectively. The therapeutic effect of "Tongyuan" acupuncture was significantly superior to that of scalp acupuncture in decreasing CRGS and CPIS, and in improving the swallowing function and raising the rate of successful extubation (P<0.05). "Tongyuan" acupuncture treatment can improve cough reflex to remove sputum, reduce pulmonary infection, enhance swallowing function, and raise the success rate of extubation in stroke patients, which is better than scalp acupuncture.

Exhaled acetone and isoprene in perioperative lung cancer patients under intensive oral care: possible indicators of inflammatory responses and metabolic changes.

One of the most severe complications of lung resection is postoperative pneumonia, and its prevention and prediction are critical. Exhaled acetone and isoprene are thought to be related to metabolism; however, little is known on their relationship with bacteria living in the oral cavity or their meaning in the acute phase in perioperative lung cancer patients. We measured acetone and isoprene in exhaled breath of 13 Japanese patients with lung cancer (3 women and 10 men, age range 62-82 years, mean 72.4 years) before breakfast during hospitalization, and compared with two acute-phase proteins, C-reactive protein (CRP) and albumin in blood serum, as well as the total number of bacteria in saliva and their activity to produce acetone and isoprene. Before operation, intensive oral care was carried out for each patient to prevent postoperative pneumonia, and swallowing and cough reflexes were measured for 12 of 13 patients to assess risk of postoperative pneumonia. Breath and saliva were sampled before intensive oral care (T1), after oral care but before operation (T2), and after operation (T3) during hospitalization. The total number of oral bacteria in saliva decreased significantly from T1 to T2 among 13 patients. No acetone or isoprene was detected from saliva after in vitro incubation under anaerobic or aerobic conditions, but both acetone and isoprene were detected in breath. After operation, breath acetone correlated significantly with CRP (Spearman's ρ = 0.559, P = 0.03), but not with albumin. Breath isoprene correlated significantly with albumin (Spearman's ρ = 0.659, P = 0.008), but not with CRP after operation. Although the number of subjects was small, our results support the hypothesis that breath acetone and isoprene may be related with these acute-phase proteins, which reflect inflammatory reactions and subsequent changes in metabolism in the early postoperative phase of lung resection.

Acute Respiratory Tract Infections/Acute Bronchitis

Was ist neu? Stand der Dinge Die akute Bronchitis ist eine selbstlimitierende, akute Entzündung der Atemwege und tritt meistens im Rahmen einer viral bedingten Erkältung in Erscheinung. Obwohl sie in der Regel nach zwei bis drei Wochen selbstlimitierend abklingt, sind viele Patienten ungeduldig und fordern mitunter eine Antibiotikabehandlung. Diagnostik Anamnese und körperliche Untersuchung sind bei unkomplizierter akuter Bronchitis ausreichend. Bei älteren, multimorbiden oder immunsupprimierten Patienten oder Auffälligkeiten bei Vitalparametern ist eine weitergehende Differenzialdiagnostik notwendig. Die Bestimmung des Procalcitonins konnte in prospektiven Studien bisher keinen sicheren Nutzen zeigen. Therapie Bei der unkomplizierten akuten Bronchitis erfolgt eine symptomatische Therapie. Um Fehlverschreibungen zu verhindern, sind die Edukation von Arzt und Patient sowie eine Verschreibung erst bei Zweitkontakt erfolgreich. Die antibiotische Therapie bleibt einem Risikokollektiv vorbehalten. Es bleibt abzuwarten, ob mittels Procalcitonin in Zukunft Patienten bestimmt werden können, bei denen auf eine antibiotische Therapie verzichtet werden kann.

Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma

Cough is a common and troublesome symptom in asthmatic patients, but little is known about the neuronal pathways that trigger cough. The mechanisms by which airway inflammation, airway hyperresponsiveness, and variable airflow obstruction cause cough are unclear. We sought to investigate the effects of allergen exposure on cough reflex sensitivity. We performed a 9-visit, randomized, single-blind, placebo-controlled, 2-way crossover study comparing cough responses to inhaled capsaicin in patients with mild atopic asthma after allergen challenge compared with diluent control. Full-dose capsaicin challenge was performed at screening to determine the capsaicin dose inducing a half-maximal response, which was subsequently administered at 30minutes and 24hours after inhaled allergen/diluent challenge. Spontaneous coughing was measured for 24hours after allergen/diluent. Methacholine challenge and sputum induction were performed before and after allergen/diluent challenge. Twelve steroid-naive subjects completed the study (6 female subjects; mean age, 34.8years). Allergen inhalation caused both an early (mean±SD, 38.2%±13.0%) and late (mean±SD, 23.7%±13.2%) decrease in FEV1 and an increase in sputum eosinophil counts 24hours later (after diluent: median, 1.9% [interquartile range, 0.8% to 5.8%]; after allergen: median, 14.9% [interquartile range, 8.9% to 37.3%]; P=.005). There was also an increase in capsaicin-evoked coughs after allergen exposure compared with diluent at both 30minutes (geometric mean coughs, 21.9 [95% CI, 16.5-29.20] vs 12.1 [95% CI, 8.3-17.7]; P<.001) and 24hours (geometric mean coughs, 16.1 [95% CI, 11.3-23.0] vs 9.8 [95% CI, 6.1-15.8]; P=.001). Allergen exposure was also associated with an increase in spontaneous coughs over 24hours. Allergen-induced bronchoconstriction and airway eosinophilia result in increased cough reflex sensitivity to capsaicin associated with an increase in 24-hour spontaneous coughing.

Traffic-related air pollution induces non-allergic eosinophilic airway inflammation and cough hypersensitivity in guinea-pigs.

The pathogenesis and pathophysiology of eosinophilia-related chronic cough such as non-asthmatic eosinophilic bronchitis and cough variant asthma are still not clear. This study is to examine the potential role of traffic-related air pollution (TRAP) in eosinophilic inflammation and cough responses. Non-sensitized guinea-pigs were exposed to TRAP in an urban traffic tunnel or kept in a filtered air environment for 7 or 14days. Reflexive cough was measured using citric acid and allyl isothiocyanate (AITC) challenges, respectively. Spontaneous cough counting was determined using audio recording and a waveform analysis. Airway inflammation was evaluated using differential cells in bronchoalveolar lavage fluid (BALF) and lung histopathology. To further elucidate the relationship between airway inflammation and cough hypersensitivity, a subgroup of those exposed for 14days received a dexamethasone treatment. Compared to reflexive cough count (mean (95% confidence interval) in 10minutes) provoked by the AITC challenge for the unexposed animals (3.1 (1.7-4.5)), those were increased significantly following both the 7-day (12.0 (6.8-17.2), P<0.01) and the 14-day (12.0 (6.4-17.6), P<0.01) TRAP exposure. The effect provoked by the citric acid challenge was more profound following the 14-day exposure (26.0 (19.5-32.5) vs 3.8 (1.5-6.0) for the control, P<0.001). TRAP exposures enhanced spontaneous cough events, caused a significant increase of eosinophils and neutrophils in BALF and resulted in a dramatic eosinophilic infiltration in submucosal layer of trachea and bronchus, which can be inhibited significantly by dexamethasone treatment. TRAP exposures induced cough hypersensitivity and non-allergic eosinophilic inflammation of airways in guinea-pigs. This study highlights the potential mechanisms of eosinophilia-related chronic cough that can be induced by traffic-related air pollution.

Sedation induced by antiepileptic drugs polytherapy: A note of caution during anesthesia.

Sir, Sedation is a common complaint among patients with epilepsy taking antiepileptic drugs (AEDs). This side-effect is compounded in patients taking multiple AEDs.[123] An 18-year-old male presented with history of seizures (since day 3 of life) refractory to multiple AEDs. He was taking twice daily doses of valproate 500 mg, clonazepam 20 mg, oxcarbazepine 450 mg, and levetiracetam 1500 mg; and zonisamide 100 mg in the morning and 200 mg at bed time. He had no other co-morbidities. The patient was scheduled for vagal nerve stimulation under general anesthesia for diffuse, bilateral, non-localizing seizure foci. In the preoperative period, the patient was oriented to time, place, and person despite periods of mood swings, during which he became restless and aggressive. Baseline laboratory parameters including liver function tests were within normal limits. The patient was advised to continue AEDs on the morning of surgery. On arrival at the operating room (OR), he was deeply sedated and responded only to painful stimuli. The baseline vitals were BP 129/64 mmHg, HR 88/min, and SpO2 99% on room air. The bispectral index (BIS) value was found to be between 77 and 80. Anesthesia was induced with fentanyl 120 μg and propofol 100 mg, and tracheal intubation was facilitated with rocuronium 50 mg. The maintenance of anesthesia was done with O2: air (FiO2 0.5), sevoflurane (0.8–1 Minimum alveolar concentration [MAC]) along with continuous infusions of fentanyl (60 μg/h), and rocuronium (12 mg/h). However, the BIS value started decreasing progressively below 40 [Figure 1]. Accordingly, the sevoflurane dial concentration was tapered, and to our surprise, even at zero end-tidal concentration of sevoflurane and a MAC of 0, the BIS value consistently remained between 40 and 45 with no change in hemodynamic parameters. As a result, sevoflurane was avoided. Infusions of fentanyl and rocuronium were discontinued 45 min prior to completion of surgery. At the end of surgery (160 min), BIS value reached between 50 and 55. After confirming return of spontaneous respiration, neuromuscular reversal agent was administered. However, the patient was not able to follow the verbal commands even though gag and cough reflexes were intact, and spontaneous movement of all four limbs was present. Trachea was extubated at a BIS value of 65. The patient was shifted to the ICU and closely monitored. He showed gradual improvement in sensorium over the next 1 hour and started obeying verbal commands. On interrogation, the patient could not recall any intraoperative event.Figure 1: Shows the trend of bispectral index (BIS) during the intraoperative periodThrough this correspondence, we wish to highlight certain important issues with multiple AED therapy. First, many AEDs have sedation as an important side-effect, particularly at high doses. Our patient received five AEDs on the morning of surgery, and by the time he reached the OR, he was deeply sedated. As informed by his parents, it was a regular phenomenon, and after morning doses, he frequently slept till mid-afternoon. Second, loss of verbal responsiveness as end point of induction with propofol was not possible here. That is why a fixed dose of propofol was administered. Third, we also bring forth the importance of BIS monitoring in such cases to titrate drug doses. Had we not applied BIS monitoring, we would have unnecessarily administered higher concentrations of sevoflurane than required thereby causing further delay in anesthetic recovery. Fourth, one of the classical extubation criteria of obeying to commands by the patient at the end of the surgery was not followed. However, adequate return of spontaneous breathing and airway reflexes along with spontaneous movement of all four limbs were ensured. Moreover, the intraoperative period was uneventful, and no neurological worsening was expected. Finally, the patient could not recollect any intraoperative event in the postoperative period suggesting absence of awareness. Thus, patients taking multiple AEDs should be evaluated thoroughly during pre-anesthetic check-up. The modification of anesthetic drugs and doses should be done, accordingly. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Dexmedetomidine nebulization as adjuvant to lignocaine during awake flexible fiberoptic intubation

Sir, Awake fiberoptic intubation (AFOI) is recommended for patients with anticipated difficult airway, failed intubation, and unstable cervical spine injury where optimum positioning for laryngoscopy is difficult to achieve. Preparation includes obtundation of airway reflexes, adequate sedation, and anxiolysis along with preservation patent airway and adequate ventilation. Dexmedetomidine produces hypnosis, amnesia, analgesia, anxiolysis, sympatholysis, and antisialogogue effects; all of them are desired during AFOI.[1] Administration of dexmedetomidine through inhalational route could be a new promising noninvasive method. The bioavailability of dexmedetomidine is 65% and 82% through nasal and buccal mucosa, respectively, following nebulization.[2] Here, we reported a series of four cases of patients with difficult airway in which dexmedetomidine was used as adjuvant to lignocaine nebulization before awake fiberoptic bronchoscope-guided nasotracheal intubation. Written consent was taken from all patients. All these patients were scheduled for mandibular excision and reconstruction under general anesthesia. After shifting the patients to operating room, standard ASA monitor was connected and baseline was taken. Injection glycopyrrolate 0.2 mg i.m., intranasal xylometazoline 0.1%, was given 15 min prior to nebulization to each patient. Patients were nebulized with mixture of 4% lignocaine 10 ml and dexmedetomidine 1 μg/kg by using ultrasonic nebulizer for 15 min followed by fiberoptic bronchoscope-guided nasotracheal intubation. All patients received supplemental oxygen (2 l/min) through the working channel of the bronchoscope. Following intubation, general anesthesia was induced. The parameters observed include heart rate, mean arterial pressure, oxygen saturation at 0, 5, 10, 15 (end of nebulization), and 20 min (just after intubation). Other parameters were observed such as cough and gag reflexes [severity graded as no cough, slight ≤2 coughs, moderate (3–5 coughs), severe (>5 coughs)], patient comfort (cooperative, restless/minimal resistance, severe resistance/requirement for immediate general anesthesia), and signs of lignocaine toxicity. Discussion There were bradycardia and hypotension noted during nebulization in case 2 and 3 as shown in Table 1. Tachycardia was noted at 20 min in case 2 and 4. One episode of cough and gag reflex was noted in case 2. No cough, gag, and other adverse effects such as bronchospasm, seizures due to lignocaine toxicity, and oversedation were recorded in rest of cases as shown in Table 1. Patients were comfortable throughout the procedure.Table 1: Shows vitals parameter and cough/gag reflexes during intubationBrummett et al.[3] studied the effect after perineural dexmedetomidine injection and they attributed to the increased duration of analgesia to the local action of dexmedetomidine. The analgesic effect of dexmedetomidine was not reversed by a ∞2-adrenoceptor antagonist (prazosin or idazoxan), hence confirming its local site of action. Hence, we hypothesize that dexmedetomidine nebulization provides surface analgesia to airway mucosa in addition to its systemic effect due to its effects on peripheral nerve endings. We could not measure systemic levels of the drugs due to lack of this facility in our institute. Hence, we limited the maximum dose of lignocaine to 400 mg and dexmedetomidine 1 μg/kg. For validation of our hypothesis, we further require randomized controlled studies. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.